Azasugar-Based MMP/ADAM Inhibitors as Antipsoriatic Agents

Hideki Moriyama, Takahiro Tsukida, Yoshimasa Inoue, Kohichi Yokota, Kohichiro Yoshino, Hirosato Kondo, Nobuaki Miura, Shin Ichiro Nishimura

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75 Citations (Scopus)

Abstract

As a part of synthetic studies on MMP (matrix metalloproteinase)/ADAM (a disintegrin and metalloproteinase) inhibitors, we have preliminarily communicated that azasugar-based compound 1a exhibited a potential inhibitory activity on some metalloprotease-catalyzed proteolytic reactions. To find promising candidates for the topical treatment of psoriasis, we investigated stability in aqueous solution of compound 1a and its derivative 1b and then optimized the P1′ substuent (2-5). In the present study, we synthesized novel derivatives of compound 1a and evaluated their inhibitory activity toward MMP-1, -3, and -9, TACE, and HB-EGF shedding, from a viewpoint of versatility of azasugars as a functional scaffold. As a result, it was found that compound 1b demonstrated desirable inhibitory activity as an antipsoriatic agent, and some of the derivatives showed selective inhibitory activity. In addition, it was found that compound 1b exhibited a significant therapeutic effect on a mouse TPA-induced epidermal hyperplasia model. Therefore, compound 1b could become a promising candidate as a practical antipsoriatic agent.

Original languageEnglish
Pages (from-to)1930-1938
Number of pages9
JournalJournal of Medicinal Chemistry
Volume47
Issue number8
DOIs
Publication statusPublished - Apr 8 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Moriyama, H., Tsukida, T., Inoue, Y., Yokota, K., Yoshino, K., Kondo, H., Miura, N., & Nishimura, S. I. (2004). Azasugar-Based MMP/ADAM Inhibitors as Antipsoriatic Agents. Journal of Medicinal Chemistry, 47(8), 1930-1938. https://doi.org/10.1021/jm0304313